The interaction of the genome within this nuclear framework could act coordinately with epigenetic modifications to modulate chromatin permissive or silencing states 12, 13, 14. The regions of the genome that bind to the nuclear matrix/scaffold were named as scaffold/matrix attachment regions (S/MARs), which are usually AT-rich sequences. Nuclear matrix-associated proteins (nuclear matrix proteins), bounding to the internal nuclear matrix/scaffold, are thought to form a skeletal nuclear framework with roles in chromatin organization, DNA replication, DNA repair, transcriptional regulation, and RNA metabolism. The nuclear matrix/scaffold is thought to consist of two main structures ‘internal nuclear matrix’ and ‘nuclear shell’ (nuclear lamina). In addition, FUS is associated with active chromatin and interacts with various nuclear proteins, including nuclear matrix, C-terminal domain of RNA polymerase II, a subset of splicing and transcriptional factors 7, 8, 9, 10, 11.Ĭhromatin is thought to be organized in ordered structures consisting of radial looped domains fixed to the nuclear matrix/scaffold, which is a proteinaceous fibrogranular framework resistant to high salt and detergent extraction. Although the etiological significance of cytoplasmic inclusion remains elusive, FUS localizes mainly in the nucleus where it plays a variety of roles including transcriptional regulation, RNA metabolism (splicing, transport, translation, and degradation), and DNA damage repair 1, 2, 3, 4. N-terminal QGSY and G-rich region is low-complexity (LC) domain that is implicated in prion-like polymerization to form nonmembranous compartments such as RNA granules 5, 6. Various mutations in FUS-related familial ALS/FTD patients are clustered in C-terminal NLS, leading to cytoplasmic mislocalization and inclusion 1, 2, 3, 4. FUS is a nucleo-cytoplasmic shuttling protein with multiple domains consisting of N-terminal Gln-Gly-Ser-Tyr (QGSY) rich region, Glycine (G)-rich region, RNA recognition motif (RRM), two Arg-Gly-Gly (RGG)-rich repeats, zinc finger motif, and C-terminal nuclear localization signal (NLS). These findings indicate SAFB1 could be a FUS’s functional platform in chromatin compartment to regulate RNA splicing and ligand-dependent transcription and shed light on the etiological significance of nuclear matrix-associated proteins in ALS pathogenesis.įUS (Fused-in-sarcoma), one of causative genes for familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), encodes a multifunctional DNA/RNA binding protein. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. FUS and SAFB1 also interact with Androgen Receptor (AR) regulating ligand-dependent transcription. ![]() In addition, depletion of SAFB1 reduced FUS’s localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. ![]() N-terminal SAP domain of SAFB1, a DNA-binding motif, was required for its localization to chromatin-bound fraction and splicing regulation. FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD).
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